Initially, the wall of the primary tubular heart consists of the two epithelial derived from the fused heart fields, i.e. the endocardium and myocardium. Sandwiched between is the cardiac jelly ECM. At this point, there is no blood vessels and the myocardium has no interstitium (connective tissue). These structures appear following the formation of a third epithelial layer, the epicardium, on the surface of the myocardium. Despite its relevance to cardiac morphogenesis, virtually nothing is known about the mechanisms that regulate epicardial transformation into mesenchymal EPDC (epicardially derived cells) that express different lineage markers. The similarities between the endocardium and the epicardium are remarkable. Besides being formed at the same axial level on either side of the myocardium, the same shape changes that precede endocardial transformation occur in epicardium aswell. So does the expression of many of the same genes or proteins including four that had special implications for endocardial-mesenchyme transformation. These observations form the basis of overall hypothesis that the myocardium is the regulatory of both endocardial and epicardial transformation into invasive mesenchymal populations. Major unresolved questions include: (i) if the epicardium of each limb of the U-shaped heart is derived from a common progenitor, (ii) whether the epicardial EMTs of both limbs are a purely intrinsic of extrinsically regulated process or a combination of both, (iii) why epicardial EMTs occur at specific axial levels within each limb, and (iv) if the various precursors for the different lineages of EPDC are integrated into the epicardium of both limbs. Specific hypotheses to address these questions are proposed: 1) The epicardial epithelium of the outlet (anterior limb) is a late-forming structure derived from an anterior heart forming field located at the junction of the distal end of the heart and the aortic sac. 2) The myocardium of each cardiac limb secretes signals (e.g. bone morphogenetic protein-2 and/or -4) that induce epicardial epithelium at specific axial levels to transform into mesenchyme cells (EPDC) that are committed to different lineages. 3) A novel intracellular protein, ES130, essential for endocardial EMT is a downstream target of myocardial signaling in the epicardium and is required to sustain or complete the transformation of all competent epicardial cells ( or pro-epicardial cells) into EPDC.